PROJECT SUMMARY/ABSTRACT The calcium-sensing receptor, CaSR, is a promiscuous G protein-coupled receptor with many functions throughout the body. It is present in taste cells, but its function there is unclear. There are hypotheses suggesting that it detects the taste of (a) calcium, (b) kokumi compounds, and (c) certain amino acids. We propose to test these hypotheses, and to characterize the gustatory anatomy of CaSR. To do this, we will make and phenotype mice with a taste-specific, tamoxifen-conditional knockout (cKO) of CaSR. Some of these mice will be treated using a novel procedure?the lingual application of tamoxifen?which will ablate CaSR only in the mouth. We will then compare the taste responses of these CaSR-cKO mice with vehicle-treated littermate controls, using (a) brief-access gustometry, (b) two-bottle choice tests, and (c) gustatory electrophysiology. Taste substances surveyed will be calcium salts, kokumi compounds, amino acids, and representatives of the five basic tastes. Histological analyses of taste tissue will (a) confirm that CaSR is successfully ablated in the treated mice, (b) determine whether the cKO produces nonspecific changes in taste tissue morphology, and (c) resolve conflicts in the literature about which taste cell types express CaSR. Innovative aspects of this project include (a) the production of a taste-specific, tamoxifen-conditional knockout mouse, (b) the focus on CaSR, a probable novel taste receptor, and (c) the investigation of certain tastes? calcium, kokumi, and amino acids?that are often ignored because, without an identified receptor mechanism, they are not considered ?basic.? The findings arising from this R21 project will be a foundation for future work to elucidate CaSR's taste transduction pathway(s), its hormonal control, and its genotype-phenotype associations in humans. Characterizing the involvement of CaSR in taste perception may lead to the development of methods to improve food acceptance and thus diet, which is a critical component of good health.